Cell adhesion and migration contribute to normal processes such as differentiation, embryonic development, and wound healing as well as to the progression of diseases and pathological conditions that can result from either acute or chronic exposure to environmental toxicants, such as cancer and inflammatory responses. Cell adhesive processes result from the interactions of extracellular glycoproteins such as fibronectin, laminin, and collagens with specific receptors, the best characterized of which are the integrins. Integrins are all non-covalent, heterodimeric complexes consisting of an alpha subunit and a beta subunit. Integrins are highly regulated receptors that can exist in both an active or inactive state. Optimal ligand binding requires that an integrin is in the activated state. Integrin ligands, divalent cations (especially manganese ion), and certain monoclonal antibodies can all activate integrins directly. Integrin activators were initially identified by their ability to increase cell-substrate adhesion. We have found that they can also modulate other processes such as cell-cell adhesion and intracellular signaling pathways. The overall goal of this project is to characterize the molecular mechanisms of integrin-mediated adhesion processes, integrin activation, and the resulting downstream processes induced by adhesive proteins such as fibronectin important for the control of proliferation, adhesion, migration, and invasion of cells with a particular emphasis on human tumor cells. The primary approaches use monoclonal antibodies, protein and peptide biochemistry, physical biochemistry, and cell and molecular biology to characterize the structure and function of integrin receptors and extracellular matrix proteins. Our current work focuses on biochemical and biological consequences of integrin activation and ligand occupancy, as well as the signal transduction pathways that play roles in the modulation of cell-cell and cell-substrate adhesion. We have found that integrin-mediated cell-cell adhesion appears to be modulated by signaling processes that can be very complex and involve multiple systems including cytoskeletal proteins and PKA-mediated cAMP second messenger signaling pathways, leading to biochemical changes such as protein phosphorylation and intracellular pH.